Osmolyte-induced folding of an intrinsically disordered activation function subdomain of glucocorticoid receptor.
Intrinsically disordered (ID) regions are disproportionately higher in cell-signaling proteins, suggesting an important role in their regulatory capacity. Activation domains of many transcription factors exist in ID conformation(s). It has been suggested that large flexible regions in ID activation domains have an advantage over proteins with ordered conformations such that ID regions/domains can make more efficient interactions with their target partners. The major activation function-1 (AF1) region, located in the N-terminal domain of several steroid receptors, including the glucocorticoid receptor (GR) possess ID sequences. Recently, we reported that osmolytes fold AF1 into functionally active conformation. Most of known AF1:coregulatory proteins interactions take place in a core subdomain (AF1(C)) that is indispensible for AF1-mediated GR activity. However, it is not known whether osmolytes can induce functionally folded conformation in AF1(C). In this study we have found that a naturally occurring osmolyte, trimethylamine-N-oxide, can cooperatively fold AF1(C) into a compact structure.
Kumar
Raj
R
Division of Gastroenterology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555-0655, USA. rakumar@utmb.edu
D006801:Humans; D008744:Methylamines / Q000494:pharmacology*; D016877:Oxidants / Q000494:pharmacology*; D017510:Protein Folding; D017434:Protein Structure, Tertiary / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*
D008744:Methylamines; D016877:Oxidants; D011965:Receptors, Glucocorticoid; C005855:trimethyloxamine